ObjectiveTo investigate the mechanism through which Wendan Tang ameliorates atherosclerosis （AS） in mice by regulating ferroptosis via the Janus kinase 2（JAK2）/signal transducer and activator of transcription 3 （STAT3） signaling pathway. MethodsTwelve 8-week-old male C57BL/6J mice of SPF grade were selected as the blank control group and fed a standard diet. Additionally， sixty age-matched male apolipoprotein E knockout （ApoE^-/-） mice of the same strain and SPF grade were selected and assigned through a random number table into the following groups （n=12 per group）： a model group， a low-dose （3.9 g·kg^-1·d^-1） Wendan Tang group， a medium-dose （7.8 g·kg^-1·d^-1） Wendan Tang group， a high-dose （15.6 g·kg^-1·d^-1） Wendan Tang group， and an atorvastatin calcium （0.01 g·kg^-1·d^-1） group. All ApoE^-/- mice were fed a high-fat diet for the modeling of AS. Starting from week 9， the blank and model groups were administrated with an equal volume of normal saline by gavage， and the remaining groups with corresponding agents by gavage. After 8 weeks of intervention， samples were collected for analysis. Oil red O staining and Masson staining were used to observe lipid deposition in the aorta， and hematoxylin-eosin （HE） staining was employed to examine AS plaque formation. The serum levels of total cholesterol （TC）， triglycerides （TG）， low-density lipoprotein cholesterol （LDL-C）， and high-density lipoprotein cholesterol （HDL-C） were measured by an automatic biochemical analyzer. The serum levels of interleukin-6 （IL-6）， tumor necrosis factor-α （TNF-α）， superoxide dismutase （SOD）， malondialdehyde （MDA）， and reduced glutathione （GSH） were determined by enzyme-linked immunosorbent assay （ELISA）. The level of Fe²⁺ in the aortic tissue was measured by ELISA. Western blot was performed to determine the protein levels of JAK2， phosphorylated JAK2 （p-JAK2）， STAT3， phosphorylated STAT3 （p-STAT3）， solute carrier family 7 member 11 （SLC7A11）， and glutathione peroxidase 4 （GPX4） in the aortic tissue. Real-time quantitative polymerase chain reaction （Real-time PCR） was utilized to measure the mRNA levels of JAK2， STAT3， SLC7A11， and GPX4 in the aortic tissue. ResultsCompared with the blank control group， the model group exhibited increased aortic plaque number and area， enhanced lipid deposition， elevated serum levels of TC， TG， LDL-C， TNF-α， IL-6， and MDA （P<0.05， P<0.01）， declined serum levels of HDL-C， SOD， and GSH， and downregulated protein levels of SLC7A11 and GPX4 in the aortic tissue （P<0.05， P<0.01）. The aortic tissue of the model group exhibited an elevated Fe²⁺ level and upregulated protein levels of p-JAK2 and p-STAT3 and mRNA levels of JAK2 and STAT3 （P<0.05， P<0.01）. Compared with the model group， low-， medium-， and high-dose Wendan Tang， as well as atorvastatin calcium， significantly attenuated these pathological alterations. Specifically， the treatments decreased aortic plaque burden and lipid deposition and lowered serum TC， TG， LDL-C， TNF-α， and MDA levels （P<0.05， P<0.01）. Concurrently， these interventions raised serum HDL-C， SOD， and GSH levels， upregulated the protein levels of SLC7A11 and GPX4 in the aortic tissue （P<0.05， P<0.01）， reduced the Fe²⁺ level， and downregulated the protein levels of p-JAK2 and p-STAT3 and the mRNA levels of JAK2 and STAT3 in the aortic tissue （P<0.05， P<0.01）. ConclusionWendan Tang ameliorates aortic lesions， dyslipidemia， and oxidative stress， decreased the phosphorylation levels of JAK2/STAT3， and increased the expression of SLC7A11 and GPX4 in the mouse model of AS. The results suggest that the anti-AS effect of Wendan Tang may be associated with the modulation of the JAK2/STAT3 signaling pathway and inhibition of ferroptosis.